Endogenous replication stress creates a unique therapeutic window for ALC1 targeting

ABSTRACT: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for homologous recombination-deficient (HRD) high-grade serous ovarian cancers. However, their durable benefit is severely limited by resistance and hematologic toxicity. PARPi are also largely ineffective in homologous recombination-proficient tumors, especially CCNE1-amplified cancers, which remain therapeutically intractable. We show that loss of the chromatin remodeler Amplified in Liver Cancer 1 (ALC1) markedly sensitizes serous ovarian cancer cells, xenografts, and patient-derived models to PARPi across both HRD and CCNE1-amplified contexts. Unlike other PARPi sensitizers, ALC1 depletion circumvents clinically relevant PARPi resistance while sparing BRCA wild-type and heterozygous nonmalignant cells, revealing an unusually

SUBMITTER: Lindsey, N. Aubuchon 

PROVIDER: S-SCDT-10_1038-S44319-026-00966-3 | biostudies-other |

REPOSITORIES: biostudies-other